Carboxyl-terminal fragments of Alzheimer β-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells

被引:59
作者
Chen, FS
Yang, DS
Petanceska, S
Yang, A
Tandon, A
Yu, G
Rozmahel, R
Ghiso, J
Nishimura, M
Zhang, DM
Kawara, T
Levesque, G
Mills, J
Levesque, L
Song, YQ
Rogaeva, E
Westaway, D
Mount, H
Gandy, S
St George-Hyslop, P
Fraser, PE
机构
[1] Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Lab Med & Pathobiol, Toronto, ON M5S 3H2, Canada
[2] Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Med Biophys, Toronto, ON M5S 3H2, Canada
[3] Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Med, Toronto, ON M5S 3H2, Canada
[4] Toronto Hosp, Dept Med Neurol, Toronto, ON M5S 3H2, Canada
[5] NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Dept Psychiat, Orangeburg, NY 10962 USA
[6] NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Dept Pathol, Orangeburg, NY 10962 USA
[7] Hosp Sick Children, Res Inst, Dept Pharmacol, Toronto, ON M5S 3H2, Canada
[8] Hosp Sick Children, Res Inst, Dept Genet, Toronto, ON M5S 3H2, Canada
[9] Hosp Sick Children, Dept Genet, Toronto, ON M5S 3H2, Canada
[10] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 3H2, Canada
基金
加拿大健康研究院;
关键词
D O I
10.1074/jbc.M006986200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Absence of functional presenilin 1 (PS1) protein leads to loss of gamma -secretase cleavage of the amyloid precursor protein (beta APP), resulting in a dramatic reduction in amyloid beta peptide (A beta) production and accumulation of alpha- or beta -secretase-cleaved COOH-terminal fragments of PAPP (alpha- or beta -CTFs). The major COOH-terminal fragment (CTF) in brain was identified as PAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily A beta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length beta APP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1-/- neurons las in normal cells) trafficking of beta APP to the Golgi compartment is necessary before alpha- and beta -secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual gamma -secretase catalytic activity or in other functions indirectly related to gamma -secretase catalysis (e,g. an activator of gamma -secretase, a substrate adaptor for gamma -secretase, or delivery of gamma -secretase to beta APP-containing compartments).
引用
收藏
页码:36794 / 36802
页数:9
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